Mutations in a number of ciliary genes can lead to diverse genetic diseases called ciliopathies. The ciliary gene CEP290, which encodes a multidomain coiled-coil protein, is associated with at least five different ciliopathies in human, but the consequences of its disruption in animal models are not always consistent with the diseases. Now, using zebrafish, Iain Drummond and colleagues (Cardenas-Rodriguez et al., 2021) explore whether a genetic compensation mechanism could explain the different cilia-associated phenotypes. By using morpholinos to acutely knock down Cep290 and generating a cep290 mutant by CRISPR/Cas9, they carefully characterize a range of cilia-associated phenotypes; importantly, acute Cep290 knockdown with morpholinos produces much stronger ciliary defects than genetic loss of function, despite the absence of the full-length Cep290 protein in both conditions. Applying transcriptomic analysis, the authors then identify a group of highly upregulated ciliary genes specifically in the mutant, including the small GTPases arl3 and arl13b, and the cargo adapter unc119b. Strikingly, overexpressing these factors in the morphants partially rescued body shape as well as cilia length defects. Collectively, the data suggest that, upon loss of cep290, a genetic compensation mechanism upregulates genes related to ciliary membrane transport, which could explain the largely normal cilia function in these mutants.